This invention relates to pharmaceutical compositions which provide convenient, palatable oral dosage formulations for the acid-labile dideoxy purine nucleosides such as 2',3'-dideoxyadinosine, 2'3'-dideoxyinosine, and 2',3'-dideoxyguanosine. More specifically, it relates to inclusion of specific antacid buffers which confer special advantages such as increased bioavailability, lower variability in bioavailability between patients, greater convenience, lessened potential for gastrointestinal distress, and higher patient acceptability.
Compositions containing 2',3'-dideoxyadenosine (ddA), 2'3'-dideoxyinosine (ddI), and 2'3'-dideoxyguanosine (ddG), and their triphosphates for treating retroviral infections have been disclosed. Mitsuya, et al., in U.S. Pat. No. 4,861,759 disclose the oral administration of these dideoxy purine nucleosides in the form of liquids or tablets containing antacid buffering agents so that the pH of the resultant composition is in the neutral (pH 6-pH 8) range. Specifically exemplified and claimed is an oral gavage formulation containing 0.1N acetate buffer with a pH of 6.8 to 7.2. Enteric coating of the tablets is also disclosed as an option.
The acid lability of the 2',3'-dideoxypurine nucleosides is well-known in the art and for that reason their oral administration typically requires administration on an empty stomach after ingestion of antacids. Prevention of acid-catalyzed hydrolysis of parent drug is important for these agents because their potent antiviral activity is lost in their hydrolysis by-products. Approaches to improving the acid stability of these acid-labile nucleoside derivatives have involved enteric-coated formulations, inclusion of a buffer in the pharmaceutical dosage form, and neutralization of the gastrointestinal tract just before drug ingestion by pretreatment with commercial antacids such as Maalox.RTM. or Mylanta.RTM.. Studies reported by McGowan, et al. in Reviews of Infectious Diseases, Vol. 12, Supp. 5, 5513-521 (1990) indicated that for ddI a superior approach for oral administration involves formulation of the drug at selected dose levels in combination with a fixed amount of citrate-phosphate buffer as a powder mixture. This dry mixture is enclosed in foil to provide a sachet (the "CP sachet") that must be mixed and diluted with liquid before oral ingestion.
Formulation approaches involving enteric coatings were not promising. Enteric coatings tended to reduce the nucleoside drug's bioavailability and depress peak plasma levels. High peak plasma levels of active drug are an important requirement for its clinical antiviral activity. Enteric coated formulations also were especially susceptible to a meal effect, further reducing bioavailability.
The citrate-phosphate buffered ddI formulations, which allow oral dosing, were preferred clinically for long-term therapy over the earlier available lyophilized dosage form of the drug which requires reconstitution prior to intravenous administration. These oral powder formulations for reconstitution consist of varying ddI levels combined with the same amount of buffering ingredients (about 10 g per day) regardless of final drug dose strength. All dose strength formulations thus have the same acid neutralization capacity. However, the powder blend sachets are bulky (about 20 g/dose) and inconvenient - their use causes some patient inconvenience. Reconstitution is always required prior to administration and results in a large volume of constituted solution (due to 20 g of solute) to be ingested. This salty solution can cause diarrhea and the required ingestion of about 10 g per day of soluble antacid buffers may result in systemic alkalosis when administered on a long-term basis as required, for example, in treating HIV infections.
A comparison of available oral formulations of ddI was recently reported (Hartman, et al., "Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human immunodeficiency infection. II. The effects of different oral formulations and the presence of other medications," Cli. Pharmacol. Ther., 1991; 50:278-85). With the maximum bioavailability of any buffered preparation being reported as.ltoreq.40%, the reference concludes that "an optimal preparation remains to be found." Of existing formulations, the "CP sachet" appeared to be the best oral preparation although its use caused reported diarrhea and/or hypokalemia in some patients.
It was an object of the present invention to provide pharmaceutical compositions for these acid-labile nucleoside derivatives which would allow convenient oral administration of reduced mass dosage formulations such as tablets which could be chewed and swallowed or readily dispersed in liquid for ingestion. Such a composition would also allow formulation of reduced mass sachet dosage forms.
Another objective was to find a combination of antacid buffers effective in preventing acid hydrolysis of the nucleosidic agent but whose effect on diarrhea and/or electrolyte and pH imbalances would be minimized.
A further object of the invention was to provide a pleasant tasting composition with high levels of patient acceptance and tolerability. A key to realization of these objects was in providing in a reduced mass form the same amount of bioavailable drug delivered by the bulky dry powder blend provided in the citrate-phosphate buffer sachets. Surprisingly, improved buffer systems comprising certain water-insoluble aluminum or calcium carbonates in combination with water-insoluble magnesium antacids were found to increase drug bioavailability by about 20 to 25%. Addition of reduced amounts of compatible sweetening and flavoring agents for incorporation into the improved drug-buffer composition also contributed to achieving the objects of the invention.